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Biochemical Society Transactions Dec 2022Protein synthesis is dysregulated in the majority of cancers and this process therefore provides a good therapeutic target. Many novel anti-cancer agents are directed to... (Review)
Review
Protein synthesis is dysregulated in the majority of cancers and this process therefore provides a good therapeutic target. Many novel anti-cancer agents are directed to target the initiation stage of translation, however, translation elongation also holds great potential as a therapeutic target. The elongation factor eIF5A that assists the formation of peptidyl bonds during the elongation process is of considerable interest in this regard. Overexpression of eIF5A has been linked with the development of a variety of cancers and inhibitors of the molecule have been proposed for anti-cancer clinical applications. eIF5A is the only protein in the cell that contains the post-translational modification hypusine. Hypusination is a two-step enzymatic process catalysed by the Deoxyhypusine Synthase (DHPS) and Deoxyhypusine Hydroxylase (DOHH). In addition, eIF5A can be acetylated by p300/CBP-associated factor (PCAF) which leads to translocation of the protein to the nucleus and its deactivation. In addition to the nucleus, eIF5A has been found in the mitochondria and the endoplasmic reticulum (ER) with eIF5A localisation related to function from regulation of mitochondrial activity and apoptosis to maintenance of ER integrity and control of the unfolded protein response (UPR). Given the pleiotropic functions of eIF5A and by extension the hypusination enzymes, this system is being considered as a target for a range of cancers including multiple myeloma, B-Cell lymphoma, and neuroblastoma. In this review, we explore the role of eIF5A and discuss the therapeutic strategies that are currently developing both in the pre- and the clinical stage.
Topics: Peptide Initiation Factors; Protein Biosynthesis; Protein Processing, Post-Translational; Apoptosis; Neoplasms
PubMed: 36511302
DOI: 10.1042/BST20221035 -
Anatomical Record (Hoboken, N.J. : 2007) Dec 2018Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle... (Review)
Review
Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle contraction, and developmental reprogramming. Most actin studies have focused on its regulation at the protein level, either directly or through differential interactions with over a hundred intracellular binding partners. However, numerous studies emerging in recent years demonstrate specific types of nucleotide-level regulation that strongly affect non-muscle actins during cell migration and adhesion and are potentially applicable to other members of the actin family. This regulation involves zipcode-mediated actin mRNA targeting to the cell periphery, proposed to mediate local synthesis of actin at the cell leading edge, as well as the recently discovered N-terminal arginylation that specifically targets non-muscle β-actin via a nucleotide-dependent mechanism. Moreover, a study published this year suggests that actin's essential roles at the organismal level may be entirely nucleotide-dependent. This review summarizes the emerging data on actin's nucleotide-level regulation. Anat Rec, 301:1991-1998, 2018. © 2018 Wiley Periodicals, Inc.
Topics: Actin Cytoskeleton; Actins; Amino Acid Sequence; Animals; Humans; Protein Biosynthesis; Protein Processing, Post-Translational; RNA Interference
PubMed: 30312009
DOI: 10.1002/ar.23958 -
RNA Biology Jan 2023RNA modifications play a vital role in multiple pathways of mRNA metabolism, and translational regulation is essential for immune cells to promptly respond to stimuli... (Review)
Review
RNA modifications play a vital role in multiple pathways of mRNA metabolism, and translational regulation is essential for immune cells to promptly respond to stimuli and adapt to the microenvironment. N6-methyladenosine (mA) methylation, which is the most abundant mRNA modification in eukaryotes, primarily functions in the regulation of RNA splicing and degradation. However, the role of mAmethylation in translational control and its underlying mechanism remain controversial. The role of mA methylation in translation regulation in immune cells has received relatively limited attention. In this review, we aim to provide a comprehensive summary of current studies on the translational regulation of mA modifications and recent advances in understanding the translational control regulated by RNA modifications during the immune response. Furthermore, we envision the possible pathways through which mA modifications may be involved in the regulation of immune cell function via translational control.
Topics: Protein Biosynthesis; RNA; Immune System; Protein Processing, Post-Translational; RNA-Binding Proteins; Humans; Animals; Methylation
PubMed: 37584554
DOI: 10.1080/15476286.2023.2246256 -
Trends in Neurosciences Feb 2018Persistent pain, which is poorly treated and estimated to afflict one third of the world's population, is largely mediated by the sensitization of nociceptive neurons.... (Review)
Review
Persistent pain, which is poorly treated and estimated to afflict one third of the world's population, is largely mediated by the sensitization of nociceptive neurons. This sensitization involves de novo gene expression to support biochemical and structural changes required to maintain amplified pain signaling that frequently persists even after injury to tissue resolves. While transcription-dependent changes in gene expression are important, recent work demonstrates that activity-dependent regulation of mRNA translation is key to controlling the cellular proteome and the development and maintenance of persistent pain. In this review, we highlight recent advances in translational regulation of gene expression in nociceptive circuits, with a focus on key signaling pathways and mRNA targets that may be tractable for the creation of next-generation pain therapeutics.
Topics: Animals; Chronic Pain; Humans; Nociception; Nociceptors; Protein Biosynthesis; Sensory Receptor Cells; Signal Transduction
PubMed: 29249459
DOI: 10.1016/j.tins.2017.11.006 -
Biochimica Et Biophysica Acta Mar 2016Photosystem II (PSII), a large multisubunit membrane protein complex found in the thylakoid membranes of cyanobacteria, algae and plants, catalyzes light-driven oxygen... (Review)
Review
Photosystem II (PSII), a large multisubunit membrane protein complex found in the thylakoid membranes of cyanobacteria, algae and plants, catalyzes light-driven oxygen evolution from water and reduction of plastoquinone. Biogenesis of PSII requires coordinated assembly of at least 20 protein subunits, as well as incorporation of various organic and inorganic cofactors. The stepwise assembly process is facilitated by numerous protein factors that have been identified in recent years. Further analysis of this process requires the development or refinement of specific methods for the identification of novel assembly factors and, in particular, elucidation of the unique role of each. Here we summarize current knowledge of PSII biogenesis in cyanobacteria, focusing primarily on the impact of methodological advances and innovations. This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Conrad Mullineaux.
Topics: Bacterial Proteins; Cyanobacteria; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Photosystem II Protein Complex; Protein Biosynthesis
PubMed: 26592144
DOI: 10.1016/j.bbabio.2015.11.007 -
Frontiers in Bioscience (Landmark... Jan 2015The metabolic roles for L-leucine, an essential branched-chain amino acid (BCAA), go far beyond serving exclusively as a building block for de novo protein synthesis.... (Review)
Review
The metabolic roles for L-leucine, an essential branched-chain amino acid (BCAA), go far beyond serving exclusively as a building block for de novo protein synthesis. Growing evidence shows that leucine regulates protein and lipid metabolism in animals. Specifically, leucine activates the mammalian target of rapamycin (mTOR) signaling pathway, including the 70 kDa ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4EBP1) to stimulate protein synthesis in skeletal muscle and adipose tissue and to promote mitochondrial biogenesis, resulting in enhanced cellular respiration and energy partitioning. Activation of cellular energy metabolism favors fatty acid oxidation to CO2 and water in adipocytes, lean tissue gain in young animals, and alleviation of muscle protein loss in aging adults, lactating mammals, and food-deprived subjects. As a functional amino acid, leucine holds great promise to enhance the growth, efficiency of food utilization, and health of animals and humans.
Topics: Adipose Tissue; Animals; Energy Metabolism; Humans; Leucine; Muscle, Skeletal; Protein Biosynthesis
PubMed: 25553480
DOI: 10.2741/4338 -
Current Opinion in Plant Biology Oct 2023Transposons are mobile DNA sequences that can move within the genome and integrate in new genomic locations. They are widespread in eukaryotes and prokaryotes and can... (Review)
Review
Transposons are mobile DNA sequences that can move within the genome and integrate in new genomic locations. They are widespread in eukaryotes and prokaryotes and can influence gene expression when landing within or nearby a gene. Although transposon-induced regulation of gene expression at the transcriptional level has been extensively studied, there has been less focus on regulation at the post-transcriptional and translational levels. Recent studies in maize (Zea mays) and other plant species suggest that transposon insertions can affect RNA processing, RNA stability, protein translation and protein stability. We will describe the diverse mechanisms by which transposons can influence gene expression at the post-transcriptional and translational levels, and discuss the interactions between these mechanisms.
Topics: Genes, Plant; Genomics; Protein Biosynthesis; RNA Stability; Zea mays
PubMed: 37619514
DOI: 10.1016/j.pbi.2023.102438 -
Nucleic Acids Research Feb 2020During protein synthesis, translating ribosomes encounter many challenges imposed by various types of defective mRNAs that can lead to reduced cellular fitness and, in... (Review)
Review
During protein synthesis, translating ribosomes encounter many challenges imposed by various types of defective mRNAs that can lead to reduced cellular fitness and, in some cases, even threaten cell viability. Aberrant translation leads to activation of one of several quality control pathways depending on the nature of the problem. These pathways promote the degradation of the problematic mRNA as well as the incomplete translation product, the nascent polypeptide chain. Many of these quality control systems feature critical roles for specialized regulatory factors that work in concert with conventional factors. This review focuses on the mechanisms used by these quality control pathways to recognize aberrant ribosome stalling and discusses the conservation of these systems.
Topics: Peptides; Proteasome Endopeptidase Complex; Protein Biosynthesis; RNA Stability; RNA, Messenger; RNA, Ribosomal; Ribosomes; Ubiquitination
PubMed: 31950154
DOI: 10.1093/nar/gkz1201 -
Annals of the New York Academy of... Jul 2019In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. This key process is universally conserved and... (Review)
Review
In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. This key process is universally conserved and plays a crucial role in the viability and virulence of all bacteria. It is performed by transfer-messenger RNA (tmRNA) and its protein partner small protein B (SmpB). Here, we show that tmRNA is a key molecule that could have given birth to modern protein synthesis. The traces of an ancient RNA world persist in the structure of modern tmRNA, suggesting its old origins. Therefore, since it has both tRNA and mRNA functions, tmRNA could be the missing link that allowed modern genetic code to be read by the ribosome.
Topics: Animals; Humans; Protein Biosynthesis; Protein Structure, Secondary; RNA, Bacterial; RNA, Messenger; RNA, Transfer
PubMed: 30815901
DOI: 10.1111/nyas.14035 -
Molecular and Cellular Endocrinology May 2017Androgens significantly alter muscle mass in part by shifting protein balance in favor of net protein accretion. During various atrophic conditions, the clinical impact... (Review)
Review
Androgens significantly alter muscle mass in part by shifting protein balance in favor of net protein accretion. During various atrophic conditions, the clinical impact of decreased production or bioavailability of androgens (termed hypogonadism) is important as a loss of muscle mass is intimately linked with survival outcome. While androgen replacement therapy increases muscle mass in part by restoring protein balance, this is not a comprehensive treatment option due to potential side effects. Therefore, an understanding of the mechanisms by which androgens alter protein balance is needed for the development of androgen-independent therapies. While the data in humans suggest androgens alter protein balance (both synthesis and breakdown) in the fasted metabolic state, a predominant molecular mechanism(s) behind this observation is still lacking. This failure is likely due in part to inconsistent experimental design between studies including failure to control nutrient/feeding status, the method of altering androgens, and the model systems utilized.
Topics: Androgens; Animals; Humans; Models, Biological; Muscle Proteins; Muscle, Skeletal; Protein Biosynthesis; Proteolysis
PubMed: 28237723
DOI: 10.1016/j.mce.2017.02.031